Peter Geistlich Award Recipients
Lobat Tayebi, Phd
Lobat Tayebi, Phd – Marquette University School of Dentistry
VEGF Encapsulation Through a Novel Microfluidic Technique for Bone Tissue Regeneration and Repair
Lobat Tayebi is an Associate Professor and Director of Research at Marquette University School of Dentistry. She received her PhD from University of California-Davis in 2011. She is a researcher in tissue engineering and regenerative medicine with multiple patents in the field. Her publication list comprises of more than 115 peer-reviewed articles including papers in Nature Materials and Advanced Materials. Her current research activities cover projects in treatment of complex multi-tissue oral and craniomaxillofacial defects, growth factor delivery and interfacial hard/soft tissue expansion, growth factor delivery, vascularization and stem cell seeding in patient specific 3D-bioprinted scaffolds.
Using growth factors in tissue regeneration has generated great enthusiasm and an intensive research effort leading to recent clinical trials, many of which have yielded unsatisfactory outcomes. Interestingly, the trials with the most satisfactory results have shared a common denominator: the presence of a vehicle for controlled growth factor delivery.
Blood vessels provide oxygen and nutrients for tissues and remove waste products. A reduction or loss in vascularization can lead to tissue necrosis, tissue death and organ failure. Vascular endothelial growth factor (VEGF) is an important vasculogenic and angiogenic agent which regulates signaling, proliferation and migration of endothelial cells. The VEGF pathway is critical for bone regeneration by promoting activity of bone forming cells and mobilization of involved progenitor cells.
However, the delivery of VEGF is specifically sensitive and should be localized and transported to a specific target tissue which requires a prolonged and sustained exposure to a low dose of VEGF. A bolus injection, imprecise use (off targeting), or unsatisfactory drug delivery can increase the threat of unwanted side effects and often lead to tumorigenesis. Currently, delivery systems are imperfect and limited technologies exist for precise encapsulation of VEGF and its sustained and controlled release. The use of microparticles as vehicles can provide an efficient and directed means for VEGF delivery that can be controlled, localized and released in a sustained fashion.
In this project using a new microfluidic approach, we will develop a method that creates precise customized encapsulated VEGF particles with well-regulated release rates. These particles can be embedded in scaffolds and implants designed for critically sized defects and used along with other growth factors to promote tissue regeneration and repair in oral and craniomaxillofacial injuries.
Jeremy J. Mao, DDS, PhD
Jeremy J. Mao, DDS, PhD – Columbia University, College of Dental Medicine
Novel Bone Grafting Procedures for Oral and Maxillofacial Applications
Dr. Jeremy Mao is a clinician/scientist, and currently Edwin S. Robinson Professor of Dentistry at Columbia University. Dr. Mao has published over 200 scientific articles, proceedings, book chapters and books. Dr. Mao has delivered over 360 invited, keynote and plenary lectures worldwide. Dr. Mao has been active in the field of orthopedic research, plastic surgery research and dental/craniofacial research. Dr. Mao’s laboratory has trained dozens of scientists and clinicians that are in academia, industry and government. Dr. Mao’s research group is currently funded by NIH and other grants in the areas of stem cell biology, tissue engineering and wound healing.
One of the dire needs in Oral and Maxillofacial Surgery (OMS) is craniofacial bone defects following loss of natural teeth, trauma, tumor resection and infections. Approximately over 50% of dental implant patients require ridge augmentation of resorbed alveolar bone prior to or at the time of implant placement. In OMS, autogenous bone grafts have been considered the “gold standard” for regenerative procedures. However, due to the limitation of the supply and morbidity on the secondary surgical site, a substitute to autogenous bone grafts represents an acute medical need. Various allografts, xenografts and alloplast materials have been tested for decades. To date, no bone graft products in the market can meet clinical needs.
Simon W. Young, DDS, MD, PhD
Simon W. Young, DDS, MD, PhD – University of Texas School of Dentistry at HoustonDevelopment of a Compromised Maxillofacial Wound Healing Model for Bone Graft Evaluation
Dr. Young’s research interest includes the design of materials for the promotion of bone regeneration in the craniomaxillofacial complex. He has broad experience in the fields of biomaterials, growth factor delivery, in vivo models, and characterization of bone and neovascularization. As an oral & maxillofacial surgeon with experience treating traumatic defects and pathology, Dr. Young understands the unique challenges associated with the reconstruction of complex maxillofacial wounds. By designing a novel preclinical model of compromised wound healing, Drs. Young and Kasper hope to better understand the mechanisms which prevent successful bone grafting, and use these insights to design better therapies in the future.
Despite our understanding of bone regeneration in sites with an optimized underlying physiological environment, it is still poorly understood why bone grafting fails in the setting of the compromised wound (i.e. osteoradionecrosis, multiply-operated sites, etc.). Whether the defect lies in an inadequately vascularized environment, an adversely affected (or missing) progenitor cell population, the complicating presence of bacterial contamination, or a sub-optimal cytokine milieu, the relative contributions of these factors remains to be clearly elucidated. A clinically relevant, reproducible model of compromised wound healing would be invaluable not only to study these potential mechanisms of bone graft failure, but to inform future strategies to improve bone grafting in these situations.
The studies outlined in this proposal seek to build upon our established rabbit mandibular defect model to develop a new pre-clinical model of compromised maxillofacial wound healing for application as a clinically-relevant platform for (1) the elucidation of key differences between compromised and non-compromised maxillofacial wound environments and (2) the evaluation of bone regeneration strategies in a compromised wound bed. The novel model of compromised maxillofacial wound healing will be applied in Specific Aim 1 toward elucidation of significant vascular, cellular, and cytokine expression differences between the compromised wound healing environment and non-irradiated controls. The model will then be applied in Specific Aim 2 to characterize the efficacy of various standard bone grafting materials to establish a baseline of data to facilitate future evaluation of rationally-designed bone tissue engineering materials.
Qunzhou Zhang, PhD
Qunzhou Zhang, PhD, University of Pennsylvania School of Dental Medicine
Application of NSC-like Progenitors Induced from Gingiva-derived MSCs in Facial Nerve Regeneration
Dr. Qunzhou Zhang received his PhD in Biochemistry and Molecular Biology from West China University of Medical Sciences in 2000. He is currently a senior investigator and the leading scientist in Dr. Anh Le’s laboratory at the Department of Oral & Maxillofacial Surgery, University of Pennsylvania School of Dental Medicine. The primary focus of Dr. Zhang’s current research is immunomodulatory and regenerative function of human gingiva-derived mesenchymal stem cells. His research is funded by Stephan B. Milam Research Support Grant from Oral & Maxillofacial Surgery Foundation, University of Pennsylvania Diabetes Research Center (DRC) and Schoenleber Pilot Grant from Penn School of Dental Medicine.
Fully functional recovery of facial nerve injury is a major challenge for oral surgeons. Autologous nerve grafts currently remain the gold standard for repairing injured peripheral nerves with a large gap. However, donor site morbidity, availability of donor nerve and danger of neuroma formation significantly impede their clinic application. Even though alternative allogenic grafts and bioengineered nerve conduits are used in clinic, their overall outcomes are still suboptimal. The combination of bioengineered nerve conduits and stem cells is emerging as a novel approach for peripheral nerve regeneration. Neural stem (NSC) or progenitor cells are considered an ideal candidate seed cell source for stem cell-based treatment of nerve injury, but it remains a challenge to get enough transplantable NSCs for clinical application. Expandable and multipotent neural progenitor cells (NPCs) can be induced from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), but the process is complicated and time-consuming and needs the introduction of exogenous genes, which raise concerns regarding the safety for their clinical use. Thus, generation of expandable NPC-like cells directly from somatic cells may represent an ideal approach for stem cell-based therapy of peripheral nerve injury. This work will test the hypothesis that human gingiva-derived mesenchymal stem cells (GMSCs) can be directly converted to multipotent NPC-like cells with therapeutic potentials for facial nerve defects. Specifically, we will optimize the culture conditions for induction of NPC-like cells from GMSCs and evaluate their multipotency both in vitro and in vivo. We will then use a rat model to test the therapeutic efficacy of GMSC-derived NPC-like cells on repair/regeneration of facial nerve defects. Accomplishment of this study will provide substantial evidence for the potential clinical application of GMSC-derived NPC-like cells for facial nerve regeneration.
Lucas Lu, PhD
Lucas Lu, PhD | University of Delaware
A Biomimetic Heterogeneous Synthetic Matrices for TMJ Condylar Cartilage Repair
Dr. X. Lucas Lu received his PhD in Biomedical Engineering from Columbia University with distinction in 2007. He is currently an Assistant Professor of Mechanical Engineering at the University of Delaware with a joint appointment in the Biomedical Engineering program and the Biomechanics and Movement Science program. The primary focus of Dr. Lu’s current research is cartilage tissue engineering and the prevention, treatment and rehabilitation of osteoarthritis. His research is funded by the Department of Defense, National Institutes of Health, the National Science Foundation, and the Musculoskeletal Transplant Foundation.
Temporamandibular joint (TMJ) disorders affect over 10 million Americans and are often caused by osteoarthritis (OA) or “internal derangement” of the joint. TMJ disorders pose a significant challenge in maxillofacial surgery. Here, we propose a matrix-guided, tissue engineering approach for the repair and regeneration of TMJ condylar cartilage. Our approach relies on the development of a multilayered synthetic matrix that recapitulates the anisotropic feature and the tension-compression nonlinearity. We will create a composite matrix consisting of a bottom, hyaluronan (HA)-based gel layer with spatial gradient of biochemical cues, and a top fibrous layer, de novo designed to mimic the structure and function of type I collagen. Mesenchymal stem cells residing in the matrix will receive signals from the matrix to undergo programmed differentiation in a spatial fashion. The potential of the synthetic matrix in cartilage repair will be tested in an in vitro culture system, as a TMJ osteochondral explant with physiologically relevant mechanical loading, for the generation of new cartilage tissue at the lesion site. We expect that the engineered tissue will exhibit a defined layered and zonal structure and integrate with the host tissue to fulfill the mechanical requirements of daily TMJ activities. This project represents the first effort to fabricate a biomimetic scaffold for TMJ condylar cartilage repair by replicating the unique multilayered structure found in the native tissue. The new synthetic matrix also provides a powerful in vitro platform to study the mechnobiology of TMJ chondrocytes and the developmental biology of condylar cartilage.
Pamela Yelick, PhD
Pamela Yelick, PhD | Tufts University
Biphasic Scaffolds for Alveolar Bone and Tooth Regeneration
Research in Dr. Yelick's Laboratory works to define effective methods to regenerate bone and tooth structures for craniofacial repair and reconstruction. Her models include Tissue Engineering approaches that employ novel biocompatible scaffolds seeded with dental progenitor cells, which are uniquely designed to form craniofacial bone and tooth tissues. Her successful collaborative efforts in this field have resulted in numerous published reports documenting significant progress towards achieving these goals.
Previous studies have shown that tyrosine based E1001-1K scaffolds can promote mineralized tissue formation. Here we will test whether E1001-1K scaffolds can support the formation of alveolar bone, the specialized type of jaw bone that supports dentition. Our approach involves seeding E1001-1K scaffolds with cultured dental stem cells (DSCs) derived from extracted human wisdom teeth, followed by developmental in vitro and in vivo characterizations of alveolar bone, dentin, pulp, periodontal ligament, and enamel tissue formation. Our approach is unique in that we use neural crest cell (NCC) derived dental pulp stem cells that naturally form alveolar jaw bone and tooth tissues. In contrast, mesenchymal stem cells (MSCs), commonly used for craniofacial reconstructions, are derived from the embryonic mesoderm, and do not naturally form alveolar bone, whose specialized architecture can withstand the strong mechanical forces of mastication. The ability to successfully engineer functional, durable alveolar jaw bone would be a significant improvement over current craniofacial repair techniques using bone grafts from non-NCC derived bone (fibula, rib, etc.), which eventually resorb over time. To date we have performed in vitro characterizations of DSC-seeded E1001-1K scaffolds. To continue these promising studies, here we propose studies to validate the formation of alveolar jaw bone and tooth tissues in situ, in a rat mandible critical sized defect model. The successful completion of the proposed studies will allow us to move forward to a large animal mandibular defect model, prior to pre-clinical human trials.
Mark Wong, DDS & Dr. Antonios G. Mikos, PhD
Mark Wong, DDS | University of Texas - Houston
Effects of Synthetic Graft Versus Autograft in the Generation of Autologous Free Tissue Flaps
Mark Wong is Professor and Chairman of the Department of Oral and Maxillofacial Surgery at The University of Texas School of Dentistry at Houston, where he also serves as the Director of Residency Training. Dr. Wong is currently the President of the American Academy of Craniomaxillofacial Surgeons and the President of the International Board for the Certification of Specialists in Oral and Maxillofacial Surgery. His clinical and research interests are focused on reconstructive surgery, tissue engineering of bone and the biomechanical characterization and regeneration of the temporomandibular joint. His research is funded by the NIH and the Department of Defense. Dr. Wong has served on a number of educational and research committees for AAOMS. He is a Past President of ABOMS, President-elect of the American Academy of Craniomaxillofacial Surgeons, and currently Chairs a Steering Committee for the development of an International Board for the Certification of Specialists in Oral and Maxillofacial Surgery.
Antonios G. Mikos, PhD | Rice University
Antonios G. Mikos is the Louis Calder Professor of Bioengineering and Chemical and Biomolecular Engineering at Rice University. He is the Director of the J.W. Cox Laboratory for Biomedical Engineering and the Director of the Center for Excellence in Tissue Engineering at Rice University. He received his Dipl.Eng. (1983) from the Aristotle University of Thessaloniki, Greece, and his Ph.D. (1988) in chemical engineering from Purdue University. He was a postdoctoral researcher at the Massachusetts Institute of Technology and the Harvard Medical School before joining the Rice faculty in 1992 as an assistant professor.
Mikos' research focuses on the synthesis, processing, and evaluation of new biomaterials for use as scaffolds for tissue engineering, as carriers for controlled drug delivery, and as non-viral vectors for gene therapy. His work has led to the development of novel orthopaedic, dental, cardiovascular, neurologic, and ophthalmologic biomaterials. He is the author of over 500 publications and 25 patents. He is the editor of 15 books and the author of one textbook (Biomaterials: The Intersection of Biology and Materials Science, Pearson Prentice Hall, 2008). Mikos is among the top 1 percent most cited researchers in his field. His work has been cited over 45,000 times and he has an h-index of 115.
Reconstruction of large mandibular defects following blast injury or the resection of advanced pathology is particularly challenging when both bone and soft tissue is missing. Current methods to address this problem include staged reconstruction techniques delaying hard tissue reconstruction until the soft tissue bed has been restored or the use of vascularized hard and soft tissue flaps. Donor site morbidity is significant with either approach and this concern forms the basis for a new method of regenerating bone with accompanying soft tissue.
This project leverages technology and expertise developed for a project initially funded by the Armed Forces Institute of Regenerative Medicine II initiative. Using a different site in the flap recipient as an in vivo bioreactor, synthetic materials placed into chambers will be used to generate bone flaps of customizable dimensions. These flaps are allowed to vascularize before they are harvested and transferred to the recipient defect. The Osteo Science Foundation award will provide resources to study the osteogenic capabilities of different materials implanted into a validated large animal (sheep) model as well as characterize the niche environment surrounding the bone chamber by analyzing the cell population, gene expression and other tests for osteogenic activity. Additional mechanical and histomorphometric tests will determine the load-bearing characteristics of the construct as well as morphology.
While the project is focused on mandibular defects, the same strategy could be adopted for other challenging defects in the maxillofacial region.
Tara Aghaloo, DDS, MD, PhD
Tara Aghaloo, DDS, MD, PhD | UCLA
Hard and Soft Tissue Engineering to Regenerate Mandibular Segmental Defects
Tara Aghaloo is Associate Professor in Oral and Maxillofacial Surgery at the UCLA School of Dentistry. She completed dental school at UMKC, as well as Oral and Maxillofacial Surgery residency, a medical degree, and PhD in oral biology at UCLA. Her research is in bone biology and regeneration, while maintaining an active clinical practice focusing on implants and hard and soft tissue regeneration. She is also active in professional organizations where she is a board member of the Academy of Osseointegration, and section editor of the International Journal of Oral and Maxillofacial Implants.
Through-and-through mandibular defects can arise from the treatment of various pathological processes. Failure to successfully restore mandibular continuity results in devastating consequences for patients. Reconstruction usually involves major autogenous bone grafting with potential complications and morbidity. To explore tissue engineering alternatives to hard and soft tissue grafting for mandibular continuity defects, we created a clinically relevant rat segmental defect model. Though our long-term goal is to incorporate growth factor and collagen matrix-based technologies that can translate basic science research to solve important clinical problems, the short-term goal of this proposal is to explore bone and soft tissue regeneration in animals with mandibular continuity defects. Here, we will directly evaluate rhBMP-2 with Bio-oss +/- cross-linked collagen compared to autogenous bone in mandibular defect bone and soft tissue regeneration. Our rationale is that identifying effective tissue engineering constructs for segmental mandibular defects will improve outcomes and decrease morbidity of autologous-based treatment protocols.
Tienmin Chu, DDS, Phd
Tienmin Chu, DDS, Phd | Indiana University
Thrombopoietin in Cranial Regeneration
Dr. Tien-Min Chu received his DDS degree from Kaohsiung Medical College in Taiwan. He later received his PhD in materials science and engineering from the University of Michigan in 1999. He is currently an Associate Professor of Dental Biomaterials at the Indiana University School of Dentistry. Dr. Chu’s current research activities mainly focus on cranial bone tissue engineering and the in vivo dental implant evaluations.
When large bone loss in the craniofacial area occurs, oral surgeons are faced with a very challenging reconstruction task to address both the functional and the esthetical needs for the patient. To accomplish this, they often use a combination of biological factors and graft materials. In the past, tissue engineering approach of using a three-dimensional (3D) scaffold conforming to the shape of the missing bone, loaded with mesenchymal stem cells (MSCs) and bone morphogenetic protein (BMP) has shown great promise. However, several papers since 2011 revealed serious health risks in association with the use of BMP-2. Recently, we have shown that thrombopoietin (TPO) can indirectly promote the osteogenic differentiation of MSCs and stimulate osteoblast proliferation through its action on megakaryocytes (MKs). Others have shown that TPO can potentially promote angiogenesis and endochondral ossification indirectly through MSCs. In our pilot studies, we demonstrated that TPO can induce bridging callus formation in critical-size femoral defects and can induce bone formation in cranial defects. Combined with our prior success in fabricating 3D scaffolds to carry MSCs, we hypothesize that TPO can indirectly stimulate MSCs delivered by 3D scaffolds to induce complete regeneration in critical-size cranial defects. We will first study the effects of stem cell source (bone marrow versus dental pulp), seeding density and pre-culture condition combinations on bone regeneration from stem cells seeded on scaffold and stimulated by TPO. The best combinations will then be used to investigate the dose-response of TPO in vivo. Finally, the best dose from the dose-response study will be used to study the time-response of TPO and compare that to BMP-2 in vivo. The success of this project will provide preliminary data to secure funding to allow a more comprehensive evaluation on the potentials of using TPO in this challenging task of large cranial defect regeneration.
Sidney Eisig, DDS
Sidney Eisig, DDS | Columbia University
Tracking Cells and Biomaterial Remodeling in Tissue Engineered Bone Grafts
Dr. Eisig is Chief of Hospital Dental Service at New York-Presbyterian Hospital, and the William Carr Professor and Director of Oral and Maxillofacial Surgery at both the Hospital and Columbia University School of Dental and Oral Surgery. He is a diplomat of the American Board of Oral and Maxillofacial Surgery and volunteers abroad by treating patients with cleft lip and palate on Healing the Children missions to South American countries. He practices full-scope oral and maxillofacial surgery, with a particular interest in orthognathic, craniofacial and cleft palate surgery, maxillofacial pathology and reconstruction, and pediatric oral and maxillofacial surgery.
Tissue engineered bone grafts present an attractive solution to the complexity involved in oral and maxillofacial bone grafts. Despite the functional success with tissue engineered bone grafts for bone reconstruction, little is known concerning the tissue engineered bone graft method of action and the fate of the implanted cells. In the proposed study, the implanted cell localization and contribution to bone regeneration will be investigated in a rat calvarial defect model. Utilizing genetically altered rat adipose derived stem cells (ADSCs) to fabricate our scientifically proven tissue engineered bone grafts, the objectives of the study will provide key information about the implanted stem cells concerning their function in reconstruction and site-localized safety. These results will not only benefit the clinical translation of tissue engineered bone grafts, but will provide important information to educate decisions regarding cell activity in tissue engineering applications in any targeted tissue.
Hilton Kaplan, MBBCh, FCSSA, PhD
Hilton Kaplan, MBBCh, FCSSA, PhD | Rutgers University
Decellularized Neurovascular Bundle for Craniomaxillofacial Reconstruction
Dr. Kaplan is a Reconstructive Plastic Surgeon and Biomedical Engineer with research interests in craniofacial reconstruction using decellularized tissues, and tissue engineering. He is an Associate Research Professor in the NJ Center for Biomaterials at Rutgers University, and an Adjunct Professor in Regulatory Science at the University of Southern California. Dr. Kaplan has held various clinical and research positions across academia and industry, including Senior Medical Director at Allergan (Fortune 500 healthcare) and Vice President of Clinical Sciences at LifeCell (pioneer in decellularizing dermis). He is a founding board member of the non-profits Grossman Burn Foundation, and Look at Us Alliance for Craniofacial Differences.
In traumatic facial injuries, such as large craniomaxillofacial defects and massive burn scarring, quality of life is dependent on restoring form and function. Regeneration within scarred soft tissues and large bony defects are highly dependent on robust vascular supply and sensory-motor reinnervation. Decellularized bone and soft-tissues, such as dermis and nerve grafts, are commercially available for smaller defects, i.e. those that do not require regeneration through a large 3D volume of tissue. For autologous tissues: graft take generally requires proximity of ~5mm to vascular supply, and nerve autografts exceeding 10cm should be vascularized. We therefore hypothesize that decellularized neurovascular bundles (NVBs) can be re- endothelialized and implanted into large areas of relatively avascular, asensate and/or paralyzed scar tissue; and that in so doing, these defects may be successfully reconstructed by techniques that have otherwise thus far remained suitable to smaller defects only. This research aims to make decellularized allogeneic NVBs available so that craniofacial reconstructions may be performed successfully despite the absence of local autograft vessels and nerves. This will be explored in a rodent animal model using perfusion decellularization techniques and whole-organ bioreactors for recellularization.